Discovery of lead compounds targeting the bacterial sliding clamp using a fragment-based approach

Authors

Zhou Yin, University of WollongongFollow
Louise Whittell, University of WollongongFollow
Yao Wang, University of WollongongFollow
Slobodan Jergic, University of WollongongFollow
Michael Liu, University of Technology, Sydney
Elizabeth J. Harry, University of Technology, Sydney
Nicholas Dixon, University of WollongongFollow
Jennifer Beck, University of WollongongFollow
Michael Kelso, University of WollongongFollow
Aaron Oakley, University of WollongongFollow

RIS ID

88295

Publication Details

Yin, Z., Whittell, L. R., Wang, Y., Jergic, S., Liu, M., Harry, E. J., Dixon, N. E., Beck, J. L., Kelso, M. J. & Oakley, A. J. (2014). Discovery of lead compounds targeting the bacterial sliding clamp using a fragment-based approach. Journal of Medicinal Chemistry, 57 (6), 2799-2806.

Abstract

The bacterial sliding clamp (SC), also known as the DNA polymerase III β subunit, is an emerging antibacterial target that plays a central role in DNA replication, serving as a protein–protein interaction hub with a common binding pocket to recognize linear motifs in the partner proteins. Here, fragment-based screening using X-ray crystallography produced four hits bound in the linear-motif-binding pocket of the Escherichia coli SC. Compounds structurally related to the hits were identified that inhibited the E. coli SC and SC-mediated DNA replication in vitro. A tetrahydrocarbazole derivative emerged as a promising lead whose methyl and ethyl ester prodrug forms showed minimum inhibitory concentrations in the range of 21–43 μg/mL against representative Gram-negative and Gram-positive bacteria species. The work demonstrates the utility of a fragment-based approach for identifying bacterial sliding clamp inhibitors as lead compounds with broad-spectrum antibacterial activity.

Grant Number

ARC/DP110100660

Grant Number

ARC/FT0990287